Dr. Mary Rhee's goal is to become an independent clinical investigator, focusing on the pathophysiology of diabetes-related cardiovascular disease (CVD), and its treatment/prevention strategies. Her strong educational background, didactic foundation from Emory's MSCR program, and training as an NRSA fellow, make it highly likely that she will succeed. The proposed research addresses the diabetes pandemic, reflecting an underlying rise in pre-diabetes (mainly impaired glucose tolerance, IGT), with attendant CVD risk. For this at-risk population, two major questions remain unanswered: (a) How to treat? and (b) What glucose levels confer risk? In response, she proposes three mechanistic Aims in which critical measures (CVD risk markers, beta-cell function, insulin sensitivity) will be assessed by endothelial function, oxidative stress, inflammatory markers, and "minimal model" intravenous glucose tolerance test analysis: Aim #1 - to conduct a randomized, controlled trial in IGT subjects to determine whether such critical measures can be improved by targeting mechanisms of both diabetes and CVD - using an antioxidant, an ARB, or an anti- inflammatory agent; Aim #2 - to determine whether a "high" 1-hour postchallenge glucose level is associated with abnormal critical measures even in subjects with normal glucose tolerance; and Aim #3 - to determine whether improving beta-cell function and postchallenge hyperglycemia by raising GLP-1 levels reduces the critical measures of CVD risk and beta-cell function/insulin sensitivity. To accomplish her goals, she aims to enhance her skills by conducting research that produces important new knowledge, obtaining guidance from an experienced mentor and advisory committee, taking relevant courses, and seeking feedback from scientists who are experts in appropriate fields. Her lead mentor will be Dr. Lawrence Phillips, an established investigator who has had repeated R01 funding, served as Program Director of the Emory GCRC, and has mentored numerous trainees and junior faculty who have gone on to academic careers. Her advisory committee will provide complementary guidance through expertise in the fields of CVD risk markers, oxidative stress, endothelial function, and clinical epidemiology. The K23 award should thus prepare Dr. Rhee with the mentorship and training required to compete successfully for extramural funding such as the R01 award, and ultimately to become a successful, independent, clinical investigator.